{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,9,23]],"date-time":"2025-09-23T14:08:27Z","timestamp":1758636507992,"version":"3.41.2"},"reference-count":42,"publisher":"Public Library of Science (PLoS)","issue":"7","license":[{"start":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T00:00:00Z","timestamp":1753833600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82160213"],"award-info":[{"award-number":["82160213"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:sec id=\"sec001\">\n<jats:title>Background<\/jats:title>\n<jats:p>As an anti-aging protein, although studies increasingly suggest that the Klotho plays a role in the auditory system, the link between serum Klotho levels and tinnitus remains poorly characterized. The aim of this study was to investigate the associations between serum Klotho levels and tinnitus focusing on prevalence, duration and severity in middle-aged and older adults.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec002\">\n<jats:title>Methods<\/jats:title>\n<jats:p>We performed a population-based cross-sectional study of individuals in the National Health and Nutrition Examination Survey (NHANES) 2009\u20132012 and 2015\u20132016. Univariable and multivariable logistic regression was used to evaluate the relationship between serum Klotho levels and tinnitus, with adjustment for potential confounders and further age-stratified analyses. Restricted cubic splines were applied to assess potential non-linearity in the dose-response relationship. Furthermore, Subgroup and interaction analyses were conducted to assess the consistency of this association.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec003\">\n<jats:title>Results<\/jats:title>\n<jats:p>In this research of 3280 individuals aged 40\u201379 years with a median age of 55 (IQR: 48, 62) and 48% male participants, the median serum Klotho level was 779.80pg\/mL. Multivariable logistic regression uncovered consistent inverse associations between serum Klotho levels and tinnitus incidence across progressively adjusted models (ORs: 0.68\u20130.70, <jats:italic><jats:italic>p<\/jats:italic><\/jats:italic>\u2009=\u20090.009\u20130.01). Age-based stratified analyses suggested the strongest effect was observed in individuals aged 50\u201359 years (full model ORs: 0.55, <jats:italic><jats:italic>p<\/jats:italic><\/jats:italic>\u2009=\u20090.046). A marginally significant protective effect was observed in the 60\u201369 age group (unadjusted OR=0.62, 95% CI: 0.39\u20131.00, <jats:italic><jats:italic>p<\/jats:italic>\u2009<\/jats:italic>=\u20090.050). Serum Klotho levels showed no significant correlation with tinnitus severity, while a potential association with the duration of tinnitus was observed (<jats:italic><jats:italic>p<\/jats:italic><\/jats:italic>\u2009=\u20090.058). Additionally, restricted cubic spline analysis revealed a linear inverse association between Klotho and tinnitus risk stratified by age (all <jats:italic><jats:italic>p<\/jats:italic><\/jats:italic> for nonlinear &gt;0.15). Finally, subgroup and interaction analyses revealed no significant effect modification (all <jats:italic><jats:italic>p<\/jats:italic><\/jats:italic>-interaction &gt;0.1).<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec004\">\n<jats:title>Conclusion<\/jats:title>\n<jats:p>Serum Klotho concentrations showed a consistent inverse association with tinnitus prevalence in US adults, with the strongest effect observed in individuals aged 50\u201369 years.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pone.0327228","type":"journal-article","created":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T17:29:31Z","timestamp":1753896571000},"page":"e0327228","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":1,"title":["Association of serum Klotho with tinnitus prevalence, duration and severity: A cross-sectional study in middle-aged and older adults"],"prefix":"10.1371","volume":"20","author":[{"given":"Ke-Jiang","family":"Du","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bin-Yu","family":"Mo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tao","family":"Hou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Long","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Deng-Rong","family":"Su","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7156-2893","authenticated-orcid":true,"given":"Shi-Hua","family":"Yin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2025,7,30]]},"reference":[{"key":"pone.0327228.ref001","doi-asserted-by":"crossref","first-page":"1427672","DOI":"10.3389\/fnut.2024.1427672","article-title":"Does tinnitus amplify the effects of healthy eating patterns and physical activity on the sleep disturbance or sleep insufficiency, based on the case study of NHANES survey in the United States","volume":"11","author":"J Chen","year":"2024","journal-title":"Front Nutr"},{"issue":"9904","key":"pone.0327228.ref002","doi-asserted-by":"crossref","first-page":"1600","DOI":"10.1016\/S0140-6736(13)60142-7","article-title":"Tinnitus","volume":"382","author":"D Baguley","year":"2013","journal-title":"The Lancet"},{"issue":"3","key":"pone.0327228.ref003","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1097\/AUD.0000000000001306","article-title":"Associations between physical activity, tinnitus, and tinnitus severity","volume":"44","author":"S Chen","year":"2023","journal-title":"Ear Hear"},{"issue":"1","key":"pone.0327228.ref004","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1186\/s12916-023-02998-1","article-title":"Ageing as risk factor for tinnitus and its complex interplay with hearing loss-evidence from online and NHANES data","volume":"21","author":"L Reisinger","year":"2023","journal-title":"BMC Med"},{"issue":"6655","key":"pone.0327228.ref005","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1038\/36285","article-title":"Mutation of the mouse klotho gene leads to a syndrome resembling ageing","volume":"390","author":"M Kuro-o","year":"1997","journal-title":"Nature"},{"issue":"10","key":"pone.0327228.ref006","article-title":"\u03b1-Klotho expression in human tissues","volume":"100","author":"K Lim","year":"2015","journal-title":"J Clin Endocrinol Metab"},{"issue":"5742","key":"pone.0327228.ref007","doi-asserted-by":"crossref","first-page":"1829","DOI":"10.1126\/science.1112766","article-title":"Suppression of aging in mice by the hormone klotho","volume":"309","author":"H Kurosu","year":"2005","journal-title":"Science"},{"issue":"4","key":"pone.0327228.ref008","doi-asserted-by":"crossref","first-page":"819","DOI":"10.1093\/ndt\/gfab340","article-title":"Klotho in kidney diseases: a crosstalk between the renin-angiotensin system and endoplasmic reticulum stress","volume":"38","author":"A Kale","year":"2023","journal-title":"Nephrol Dial Transplant"},{"key":"pone.0327228.ref009","doi-asserted-by":"crossref","first-page":"323","DOI":"10.3389\/fendo.2017.00323","article-title":"New insights into the mechanism of action of soluble klotho","volume":"8","author":"GD Dalton","year":"2017","journal-title":"Front Endocrinol"},{"issue":"4","key":"pone.0327228.ref010","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1016\/j.joto.2018.04.001","article-title":"Hearing analysis in heterozygous and homozygous klotho gene deficient mice","volume":"13","author":"N Yuan","year":"2018","journal-title":"J Otol"},{"issue":"9","key":"pone.0327228.ref011","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0107681","article-title":"FGF23 deficiency leads to mixed hearing loss and middle ear malformation in mice","volume":"9","author":"AC Lysaght","year":"2014","journal-title":"PLoS One"},{"key":"pone.0327228.ref012","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/S0378-5955(02)00483-5","article-title":"Expression of Klotho protein in the inner ear","volume":"171","author":"M Kamemori","year":"2002","journal-title":"Hear Res"},{"key":"pone.0327228.ref013","doi-asserted-by":"crossref","first-page":"1415494","DOI":"10.3389\/fnagi.2024.1415494","article-title":"The role of serum \u03b1-Klotho levels in preventing hearing impairment among middle-aged and older adults: insights from a nationally representative sample","volume":"16","author":"S Wang","year":"2024","journal-title":"Front Aging Neurosci"},{"issue":"3","key":"pone.0327228.ref014","doi-asserted-by":"crossref","first-page":"1169","DOI":"10.1002\/lary.31851","article-title":"Exploring the link between serum klotho and high-frequency hearing loss in older adults","volume":"135","author":"J Yan","year":"2025","journal-title":"Laryngoscope"},{"key":"pone.0327228.ref015","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1016\/j.ijcard.2022.11.010","article-title":"Association between serum Klotho concentration and heart failure in adults, a cross-sectional study from NHANES 2007-2016","volume":"370","author":"J Cai","year":"2023","journal-title":"Int J Cardiol"},{"issue":"3","key":"pone.0327228.ref016","article-title":"Machine learning for predicting metabolic-associated fatty liver disease including NHHR: a cross-sectional NHANES study.","volume":"20","author":"L Lin","year":"2025","journal-title":"PLoS ONE"},{"issue":"1","key":"pone.0327228.ref017","doi-asserted-by":"crossref","first-page":"16373","DOI":"10.1038\/s41598-024-67574-w","article-title":"Associations between tinnitus and body composition: a cross-sectional study","volume":"14","author":"SY Han","year":"2024","journal-title":"Sci Rep"},{"issue":"3","key":"pone.0327228.ref018","doi-asserted-by":"crossref","first-page":"775","DOI":"10.1097\/AUD.0000000000001467","article-title":"Contribution of tinnitus and hearing loss to depression: NHANES population study","volume":"45","author":"S Chakrabarty","year":"2024","journal-title":"Ear Hear"},{"issue":"6","key":"pone.0327228.ref019","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1097\/MAO.0000000000003895","article-title":"Association between cannabis use and tinnitus in US adults","volume":"44","author":"F Reyes Orozco","year":"2023","journal-title":"Otol Neurotol"},{"key":"pone.0327228.ref020","doi-asserted-by":"crossref","first-page":"1421605","DOI":"10.3389\/fnut.2024.1421605","article-title":"Association of oxidative balance score with hearing loss and tinnitus: NHANES 1999-2018","volume":"11","author":"H Lai","year":"2024","journal-title":"Front Nutr"},{"issue":"1","key":"pone.0327228.ref021","doi-asserted-by":"crossref","first-page":"102314","DOI":"10.1016\/j.amjoto.2019.102314","article-title":"An association between marijuana use and tinnitus","volume":"41","author":"ZJ Qian","year":"2020","journal-title":"Am J Otolaryngol"},{"key":"pone.0327228.ref022","doi-asserted-by":"crossref","first-page":"2507","DOI":"10.2147\/IJGM.S513497","article-title":"Inflammation-induced klotho deficiency: a possible key driver of chronic kidney disease progression","volume":"18","author":"Y Liang","year":"2025","journal-title":"Int J Gen Med"},{"key":"pone.0327228.ref023","doi-asserted-by":"crossref","first-page":"115545","DOI":"10.1016\/j.bbr.2025.115545","article-title":"Molecular mechanisms of neuroprotection: the interplay of Klotho, SIRT-1, Nrf2, and HO-1 in neurological health","volume":"485","author":"R Rana","year":"2025","journal-title":"Behav Brain Res"},{"key":"pone.0327228.ref024","doi-asserted-by":"crossref","first-page":"101766","DOI":"10.1016\/j.arr.2022.101766","article-title":"Aging-suppressor Klotho: prospects in diagnostics and therapeutics","volume":"82","author":"CR Abraham","year":"2022","journal-title":"Ageing Res Rev"},{"issue":"1","key":"pone.0327228.ref025","doi-asserted-by":"crossref","first-page":"21158","DOI":"10.1038\/s41598-023-47791-5","article-title":"Relationship between klotho and physical function in healthy aging","volume":"13","author":"E Arroyo","year":"2023","journal-title":"Sci 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Cell"},{"issue":"8","key":"pone.0327228.ref029","first-page":"4152","article-title":"Salt causes aging-associated hypertension via vascular Wnt5a under Klotho deficiency","volume":"130","author":"W Kawarazaki","year":"2020","journal-title":"J Clin Invest"},{"issue":"4","key":"pone.0327228.ref030","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1172\/JCI200419081","article-title":"Targeted ablation of Fgf23 demonstrates an essential physiological role of FGF23 in phosphate and vitamin D metabolism","volume":"113","author":"T Shimada","year":"2004","journal-title":"J Clin Invest"},{"issue":"4","key":"pone.0327228.ref031","doi-asserted-by":"crossref","first-page":"625","DOI":"10.3390\/biology12040625","article-title":"Involvement of Dmp1 in the precise regulation of hair bundle formation in the developing cochlea","volume":"12","author":"Y Wang","year":"2023","journal-title":"Biology"},{"key":"pone.0327228.ref032","article-title":"Vitamin D-deficient diet rescues hearing loss in Klotho mice","author":"MR Carpinelli","year":"2011","journal-title":"Hear Res"},{"issue":"12","key":"pone.0327228.ref033","doi-asserted-by":"crossref","first-page":"1340","DOI":"10.3109\/00016480902725254","article-title":"Age-dependent changes in the expression of klotho protein, TRPV5 and TRPV6 in mouse inner ear","volume":"129","author":"M Takumida","year":"2009","journal-title":"Acta Otolaryngol"},{"issue":"3","key":"pone.0327228.ref034","doi-asserted-by":"crossref","first-page":"222","DOI":"10.4161\/chan.27662","article-title":"Upregulation of KCNQ1\/KCNE1 K+ channels by Klotho","volume":"8","author":"A Almilaji","year":"2014","journal-title":"Channels (Austin)"},{"issue":"1","key":"pone.0327228.ref035","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1007\/s00005-023-00669-w","article-title":"A comprehensive study on the anti-cancer effects of quercetin and its epigenetic modifications in arresting progression of colon cancer cell proliferation","volume":"71","author":"M Bhatiya","year":"2023","journal-title":"Arch Immunol Ther Exp (Warsz)"},{"issue":"15","key":"pone.0327228.ref036","doi-asserted-by":"crossref","first-page":"6187","DOI":"10.18632\/aging.204210","article-title":"Artemisia argyi exhibits anti-aging effects through decreasing the senescence in aging stem cells","volume":"14","author":"T-J Ho","year":"2022","journal-title":"Aging"},{"key":"pone.0327228.ref037","doi-asserted-by":"crossref","first-page":"111376","DOI":"10.1016\/j.nut.2021.111376","article-title":"Nicotinamide retains Klotho expression and ameliorates rhabdomyolysis-induced acute kidney injury","author":"W Lin","year":"2021","journal-title":"Nutrition"},{"issue":"1","key":"pone.0327228.ref038","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1186\/s40659-016-0105-4","article-title":"Klotho sensitive regulation of dendritic cell functions by vitamin E","volume":"49","author":"NT Xuan","year":"2016","journal-title":"Biol Res"},{"issue":"23","key":"pone.0327228.ref039","doi-asserted-by":"crossref","first-page":"4230","DOI":"10.3390\/foods12234230","article-title":"Association of dietary vitamin C consumption with serum klotho concentrations","volume":"12","author":"Y Wang","year":"2023","journal-title":"Foods"},{"issue":"2","key":"pone.0327228.ref040","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1007\/s13105-023-01005-8","article-title":"Exercise-induced changes in plasma S-Klotho levels are associated with the obtained enhancements of heart rate variability in sedentary middle-aged adults: the FIT-AGEING study","volume":"80","author":"G Navarro-Lomas","year":"2024","journal-title":"J Physiol Biochem"},{"issue":"3","key":"pone.0327228.ref041","doi-asserted-by":"crossref","first-page":"167055","DOI":"10.1016\/j.bbadis.2024.167055","article-title":"Therapeutic potential of AAV-FL-Klotho in obesity: impact on weight loss and lipid metabolism in mice","volume":"1870","author":"M-J Park","year":"2024","journal-title":"Biochim Biophys Acta Mol Basis Dis"},{"issue":"4","key":"pone.0327228.ref042","doi-asserted-by":"crossref","first-page":"894","DOI":"10.3390\/biomedicines10040894","article-title":"Recombinant Klotho protein ameliorates myocardial ischemia\/reperfusion injury by attenuating sterile inflammation","volume":"10","author":"J Myung","year":"2022","journal-title":"Biomedicines"}],"container-title":["PLOS 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